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Acknowledgments: The authors thank Drs. John Yates, Thomas Dobbins, Desmond Thompson, Richard Petruschke, Douglas Watson, and Walter Straus for reviewing this manuscript and for providing helpful comments. They also thank Dr. Nicholas Bellamy for providing the AUSCAN Osteoarthritis Hand Index and Drs. Thomas Schnitzer, Marc Hochberg, Arthur Weaver, Walter Straus, and Glenn Gormley for their input into study design. In addition, they gratefully acknowledge the contribution of Kathy O'Brien for assistance with manuscript preparation and for comonitoring this trial and Dr. Martino Laurenzi for comonitoring sites outside the United States.

Several previous clinical trials have shown that rofecoxib was as effective as high doses of NSAIDs for osteoarthritis treatment (18–19). However, NSAIDs can lead to serious GI events, such as perforations, ulcers, and bleeding, as well as more common symptoms, such as dyspepsia and abdominal pain. These symptoms may lead patients to discontinue treatment or add gastroprotective medications to improve tolerability.

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Figures

Trial profile.

Cumulative incidence of discontinuation due to gastrointestinal adverse events.Top.Bottom.

The incidence among the overall study sample. The incidence among patients who used low-dose aspirin. For both parts, Kaplan-Meier curves display the time course of cumulative incidence of discontinuations due to gastrointestinal adverse events by treatment group.

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In their recent letter to the editor, Braunstein and Polis address the omission of important cardiovascular safety results from an October 2003 article on the ADVANTAGE trial in the Annals of Internal Medicine (1,2). The 2003 article by Lisse and colleagues (including Polis) reported no statistically significant differences for any cardiovascular endpoints in comparisons of Vioxx (rofecoxib) and naproxen in ADVANTAGE, a 12-week clinical trial. In fact, almost three years earlier, Merck gave the FDA a data table showing a statistically significant relative risk of 7 for cardiac events amongst patients on Vioxx compared to naproxen in the ADVANTAGE trial. The Merck data table is included in a three-page January 19, 2001 letter responding to the FDA*s request for additional information on the ADVANTAGE trial; it shows 7 serious adverse cardiac events on Vioxx (6 events adjudicated as myocardial infarction and 1 event adjudicated as sudden/unknown death) and 1 cardiac event on naproxen (1 adjudicated MI) (3). Additionally, another event in the table "reported as hypertensive heart disease and death by Merck" was re-classified by the FDA in November 2001 as a sudden/unknown death, pushing the cardiac event relative risk for Vioxx to 8 (4).

Merck*s January 19, 2001 letter and the FDA*s re-classification are emphatic evidence of Merck*s knowledge that the ADVANTAGE trial showed that Vioxx use caused an important and statistically significant excess risk of cardiac events in patients on Vioxx, namely MI and sudden/unknown death. Merck*s omission of this important risk information from its 2003 article in the Annals presents a serious public health hazard because it misled the medical community. In their Annals letter, Braunstein and Polis say that Merck's pre-defined procedures kept the case of hypertensive heart disease and death from being externally adjudicated hence, its exclusion from the APTC "cardiac event" group. Since Merck defined an external adjudication events list that kept out relevant events such as hypertensive heart disease, it was fortunate that the FDA adjudicated the case. Merck still omitted this information when they published the trial.

Underlying this already egregious omission of safety data is more deeply disturbing evidence of medicine run amok. Internal Merck documents reveal that the ADVANTAGE trial did not have a medical purpose per se. Instead, it was a "seeding trial," meant to seed the medical community with Merck's new drug before it was approved for the market. Thus, the deaths of patients on Vioxx in the trial were deaths in an unnecessary trial. The real subjects of the trial were the physician "investigators" (non-participants served as controls) chosen to participate by Merck sales representatives (5). Merck intended to promote the drug to influential doctors and their patients and analyze the prescribing information of these physician-investigators for marketing purposes. A Merck public relations supervisor instructed employees to avoid revealing the true purpose of the trial, "I ELIMINATED THE REFERENCE TO SEEDING. IT MAY BE A SEEDING STUDY, BUT LET'S NOT CALL IT THAT IN OUR INTERNAL DOCUMENTS (6)." [emphasis in original]

Merck*s conduct in designing, conducting, analyzing, and publishing the ADVANTAGE trial is disturbing at best. The ethical ramifications of deaths-on-drug in a "seeding trial" deserve a more thorough examination than is possible here. The practice of selectively reporting drug safety data is evidence of the need for complete and public disclosure - perhaps on the internet - of clinical trial data for new drugs. If anything, ADVANTAGE teaches us we cannot rely on drug companies to honestly report all of the important data.

Some documents cited in this commentary were obtained in Vioxx litigation and were previously confidential but since have been entered as evidence at trial and have been unsealed.

Conflict of Interest:

Dr. Egilman has served as an expert witness in Vioxx Litigation. Mr. Presler is employed by Dr. Egilman.

Correction

Posted on
May 5, 2006

Harold C Sox

Annals of Internal Medicine

Conflict of Interest:
None Declared

We recently published a letter by Egilman and Presler (1) that cited a letter from a Merck & Co. Inc. official to the US Food and Drug Administration (FDA) (reference 3 in the Egilman and Presler letter). The cited letter reported patients that Merck & Co. Inc. had adjudicated as having had a myocardial infarction (6 patients) and sudden death (one patient) while on Vioxx during the ADVANTAGE trial (2). Dr. Braunstein, another Merck & Co. Inc official, reviewed the cited letter at our request and wrote to say that it contained an error. The correct numbers of adjudicated events were 5 myocardial infarctions and 2 sudden deaths, as documented by materials submitted by Merck & Co. Inc. to the FDA along with the letter that contained the error. Table 2 of a Letter to the Editor from Dr. Braunstein also contains the correct number of events (3).

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